The effect of diltiazem on the disposition of encainide and its active metabolites.

The disposition of encainide is under genetic control. In extensive metabolizers, the drug undergoes extensive first-pass metabolism to form the active metabolites O-desmethylencainide (ODE) and 3-methoxy-O-desmethylencainide (MODE). Because diltiazem is a known inhibitor of hepatic oxidative metabolism, the disposition of encainide and its metabolites was studied in eight extensive metabolizers and one poor metabolizer before and after administration of 90 mg diltiazem every 8 hours for 10 days. After diltiazem, the encainide serum AUC values increased in seven of the eight extensive metabolizers, and the percent recovery of encainide in urine increased by 69%. There were no apparent changes in the serum AUC values of the metabolites, suggesting that diltiazem may alter both the formation and the elimination clearances of the metabolites to a similar degree. In the poor metabolizer, encainide serum AUC increased 33% during treatment with diltiazem, but ODE and MODE could not be reliably quantitated. The subjects had no change in QRS, QTc, or JTc intervals after administration of diltiazem. Diltiazem inhibited the first-pass metabolism of encainide, resulting in increased bioavailability. This appeared to be caused by the inhibition of debrisoquin 4-hydroxylase and impairment of other unmeasured metabolic pathways for encainide. However, because no change occurs in the systemic exposure to the active metabolites, dosage adjustments in extensive metabolizers are probably not required for patients receiving combination encainide and diltiazem therapy.